Current events throughout the world underscore the growing threat of different forms of terrorism, including radiological or nuclear attack. In the event of an attack, radiation exposures will be heterogeneous in terms of both dose and quality, depending on the type of device used and each victim's location relative to the radiation source. Acute effects of high-dose radiation include changes in peripheral blood cell numbers, immune suppression, mucosal damage (gastrointestinal and oral), and potential injury to other sites such as the bone marrow, lung, kidney and central nervous system (CNS). Long-term effects, as a result of both high- and low-dose radiation, include dysfunction or fibrosis in a wide range of organs and tissues and cancer. Early triage of suspected radiation over-exposed individuals is needed to determine individuals requiring immediate medical treatment.
One of the major tasks of first responders and medical personnel is to determine the internal and external radiation doses received by victims. This critical information provides diagnostic information to the treating physicians and provides exposure assessments for individuals at the site of the incident (such as first responders and medical staff). For example, hematological and blood chemistry bioindicators have been used in radiation exposure assessment (Blakely, 2005). Blood lymphocyte counts decline after radiation exposure in a dose dependent manner. In parallel, neutrophil (granulocyte) cell counts demonstrate an early rise followed by a steep decline following medically significant radiation exposure doses. Blakely and colleagues have developed radiation casualty software applications, including: Biodosimetry Assessment Tool (BAT) (Sine, 2001; Salter, 2004) and First-Responder Radiological Assessment Triage (FRAT), using MS Windows or Palm-based operating systems to support medical recording and triage. In the FRAT application, a multiple parameter triage feature permits an integrated and weighted assessment of these various biological exposure indicators.
The current methods used for estimating the radiation dose include time to emesis, lymphocyte depletion kinetics, cytogenetic changes, and location-based or physical dosimeter-based dose estimates. The currently available methodologies, however, are lacking the necessary quantitative indices to rapidly identify exposed individuals, as well as those who could benefit from immediate medical treatment.
Ionizing radiation elicits a number of detectable changes at the molecular, cellular and physiological level in exposed organisms. These biological parameters have been called biomarkers. Biomarkers of radiation exposure are biological parameters for which a dose-response relationship can be established and can be broadly referred to as biodosimeters. One such biodosimeter is the effect of ionizing radiation on expression patterns of proteins, as well as modifications in proteins.
The human genome has some 30,000 to 50,000 genes that represent the template for many more proteins, generally with proteomic patterns specific to cell types and tissues. Biological monitoring of molecular biomarkers can provide valuable radiation exposure assessment.
Radiation-responsive protein targets, typically measured in peripheral blood but in certain cases other body fluids (urine, saliva, etc.) are measured using immunoassays, including the conventional sandwich or variations of the enzyme-linked immunosorbent assay (ELISA), microsphere-based immunoassay (Luminex), lateral flow test strips, protein arrays, etc. However, as noted above, the measurement of any one radiation-responsive protein target alone does not provide the necessary quantitative indices to identify individuals exposed to radiation.
Hoffman and colleagues reported radiation-induced increases of serum salivary amylase in 41 patients, following either whole-body irradiation or irradiation of the head and neck region (Hoffmann, 1990). Becciolini and colleagues advocate the use of biochemical (e.g., serum salivary amylase and tissue polypeptide antigen) dosimetry for prolonged spaceflights (Becciolini, 2001). Bertho and colleagues irradiated non-human primates at doses ranging from 2 to 8 Gy, using whole-body or partial-body irradiation to assess a candidate plasma protein biomarker (Flt3-ligand) as an indicator of bone marrow damage for the management of accidental radiation-induced aplasia (Bertho, 2001). C-reactive protein (CRP) and other serum biomarkers, derived primarily from the liver, of acute phase reaction or inflammation have been proposed as radiation biodosimeters (Mal'tsev, 1978; Koc, 2003).
There remains a need in the art for a rapid means of assessing radiation injury and exposure in a patient, so that the most effective treatment can be provided to the subject. Although the prior art methods of measuring a single biomarker provide some information regarding a subject's exposure to radiation, the information provided is not sufficient to make an adequate diagnosis of the level of the subject's exposure. Furthermore, the information provided is not sufficient to help a clinician develop the best possible means of treatment for each subject individually and depending on their level of exposure.